1. Field of the Invention
The present invention relates to a method for treating movement disorders using deep brain stimulation (DBS), and to a method of identifying an area of the brain to be targeted by DBS in the treatment of movement disorders.
2. Description of Related Art
Movement disorders refer to a number of conditions including Hypokinesia (Parkinson's disease), Hyperkinetic disorders (L-dopa induced dyskinesia, Hemiballism and Chorea), Dystonia (generalized and localized) and Tremor (Resting, Postural and Action tremor).
Parkinson's disease (PD) is a chronic, progressive neurodegenerative movement disorder. The main symptoms are tremors, rigidity, slow movement (bradykinesia), poor balance and difficulty walking. The highest prevalence of PD is in Europe and North America with around 1 to 1.5 million people being affected in the USA. Caucasian populations are affected more than others, with a prevalence of around 120-180 per 100,000 people. Symptoms of PD may appear at any age, but the average age of onset is 60. PD is rare in young people and risk increases with age. The cause of the disease is unknown, but there may be genetic factors.
PD is associated with degeneration of several neuronal modulators in the midbrain that primarily affect the motor system. These include the midbrain dopaminergic nuclei, the serotoninergic median raphe nuclei, the noradrenergic locus coeruleus and the cholinergic pedunculopontine nucleus.
At present, there is no cure for PD. Medical treatment for PD relies on a variety of drugs that stimulate dopamine receptors and although this approach may be effective for 5-10 years, therapy is complicated by motor side effects including “on/off” fluctuations and dyskinesias. With progressive degeneration of the dopaminergic system and other neuronal modulators the patient develops fluctuating responses to medical intervention. Surgery may be contemplated in patients who are poorly controlled on best medical therapy.
Hyperkinetic Disorders are sudden rapid involuntary and purposeless movements that typically intrude into the patient's normal activity. These movements may be both axial and peripheral. Examples of hyperkinetic disorders include L-Dopa dyskinesia, which is a complication of PD, Chorea and Hemiballism, which may result from brain lesions involving the basal ganglia. There are no effective medical treatments for these conditions.
Dystonia is a postural disorder characterized by involuntary muscle contractions affecting various parts of the body including the limbs, trunk, shoulders, face and neck.
Tremor is involuntary oscillatory movements produced by alternating contractions of agonist and antagonist muscles. These movements can affect the proximal and distal limb muscles and also the axial muscle groups. Tremor can occur at rest, with the limb maintained in a particular posture and/or during movements. Tremor can occur as a sign of PD, and as a result of lesions of the basal ganglia, midbrain or the cerebellum, but its most common form is familial Essential Tremor (ET). Medical treatments tend to variably suppress rather than abolish tremor.
At present there are various surgical treatments available for movement disorders; however, many of them involve side effects. Movement disorders are due to abnormal patterns of neuronal firing permeating the motor pathways. Surgical treatment aims to disrupt the transmission of these abnormal patterns by destroying or lesioning motor pathways or nuclei or alternatively overriding the abnormal patterns with high frequency electrical stimulation. The latter treatment is known as Deep Brain Stimulation (DBS) and is achieved by implanting an electrode into the pathways or nuclei in the brain and delivering pulsed electrical current to the tissue from an implanted pulse generator which is connected to the electrode.
A number of targets are known to be effective in the treatment of movement disorders. These include the Globus Pallidus Internus (Gpi), the Ventral Intermediate Nucleus (Vim) of the thalamus and the Subthalamic Nucleus (STN).
Lesions or DBS of the Gpi are effective for the treatment of PD, Dystonia and Hyperkinetic movements. This type of treatment has a modest effect on PD symptoms such as tremor, rigidity, bradykinesia and akinesia, but is effective in treating the motor side effects of L-dopa therapy such as dyskinesia and dystonia which allow the patient to continue on a high dose of medication.
Bilateral Gpi lesions/DBS are associated with worsening axial symptoms including deterioration in speech, swallowing and gait.
Lesions or DBS of the Vim are effective for the treatment of PD tremor but do not affect other symptoms of PD. Typically the Ventralis Intermedius (Vim) nucleus of the thalamus is the target of choice for the treatment of ET. Lesioning is reported to provide good contralateral tremor suppression. However recurrence may occur within weeks or years and long-term studies show that significant tremor persists in 17-32% of cases, (1-5). Bilateral lesions are associated with significant complications including permanent speech impairment in over 25% and memory and language dysfunction in over 50% of cases (5, 6).
Clinical studies suggest that DBS of Vim is as effective as lesioning in controlling ET (7, 8) but is likewise associated with side effects, particularly when carried out bilaterally with 30-50% patients suffering from dysarthria and dysequilibrium, (9-13) However the adverse effects associated with DBS are generally reversible by adjusting the stimulation parameters, though this may be that the expense of satisfactory tremor control. Patients treated with DBS are also reported to develop tolerance (habituation) to stimulation, despite increasing its amplitude. Patients are advised to turn the stimulators “off” at night and take stimulation holidays for weeks, in order to prevent tissue habituation, (2, 3, 14).
Lesioning of the subthalamic nucleus is known to improve tremor, rigidity, bradykinesia and akinesia and allows patients to reduce their medications, which in turn enables patients to reduce their medication. However, the Subthalamic nucleus is a small structure measuring 12 mm anteroposteriorly, 3 mm in width and 6 mm dorso-ventrally; and misplacement of a lesion can cause significant and permanent side effects. As a result, most centers prefer to implant DBS electrodes into the STN because side effects are generally reversible by reducing or stopping stimulation. DBS of the STN is currently the surgical treatment of choice for PD, nevertheless it is not without side-effects. Houeto et al., reported worsening of anxiety and depression following DBS of STN with a prevalence of anxiety in 75% of patients (15). Bemey et al., reported that DBS of STN can provoke depression in 25% with several having suicidal tendencies (16). Mania has also been reported (17). Some groups have, in addition, reported worsening of speech.
In addition to motor functions, the STN has limbic and associative functions. Disruption of these with DBS may contribute to worsening anxiety and depression seen with this treatment. Medial to the STN are fibers carrying cerebellar information to the thalamus and spread of current to these may interfere with information regarding precision movements of the larynx and hence cause worsening of speech. Stimulation of structures anterior and ventral to the subthalamic nucleus including the substantia nigra and area of Sano are associated with severe depression and mania/rage respectively.
Although bilateral simulation of the subthalamic nucleus (STN) is currently regarded as the optimum target by many neurosurgical centers the most effective therapeutic contact on a quadripolar DBS lead transfixing the STN has been reported as being one positioned at the interface of the dorsal surface of the STN and the adjacent white matter tracts (1).
Murata et al., (27) describe stimulating the posterior subthalamic area for treating proximal tremor. The treatment area selected by Murata et al. is particularly close to the prelemniscal radiation. Stimulation of this area can result in severe side effects such as speech disturbances, difficulty with precision movements and postural problems
The inventor has found that movement disorders can be treated by using DBS on a part of the brain which has not previously been targeted. This treatment avoids at least some of the problems associated with some of the prior art methods.